Chronic type B hepatitis is a serious infectious disease caused by hepatitis B virus (HBV) and prevalent throughout the world, and is closely relevant to the occurrence of hepatic cirrhosis and liver cancer. China is a high-risk area of type B hepatitis. The results of seroepidemiological survey of viral hepatitis in China from 1992 to 1995 showed that the persons carrying hepatitis B virus surface antigen (HBsAg) in China accounted for 9.7% of the population, and it was estimated that about 1.3×108 persons were HBV carriers. The study on the epidemiological situation of viral hepatitis in China demonstrated that the annual reported incidence of HB was increased from 21.9/100 thousands in 1990 to 53.3/100 thousands in 2003, showing an obvious ascending tendency (Wang Xiaojun, Zhang Rongzhen, Hu Yuansheng, et al, Surveillance of Diseases, 2004, 19(8): 290-292). Chronict type B hepatitis not only seriously affects human health, but also imposes heavy economic burden on family and society, and has become one of important public health problems in China.
The drugs useful for treating chronic type B hepatitis mainly include two varieties—immunomodulator and nucleoside DNA polymerase inhibitor (Loomba R., Liang T. J., Antivir. Ther., 2006, 11(1): 1-15). The former includes: interferon-α2b (IFN-α2b, Intron A®) and PEGylated interferon-α2a (peg-IFN-α2a, Pegasys®); the latter includes: Lamivudine (Epivir-HBV®), Adefovir Dipivoxil (Hepsera®) and Entecavir (Baraclude®). Comparatively speaking, the drugs capable of being used in clinical application for treating type B hepatitis still have quite few types and quantities. Thus, it is highly important to continuously develop new safe and effective anti-virus drugs, in particular drugs having totally new mechanism of action.
Deres et al reported heteroaromatic ring substituted dihydropyrimidine (HAP) compounds represented by Bay 41-4109, Bay 39-5493, which could take the effect of suppressing HBV replication through preventing the formation of normal nucleocapsid. The binding of this kind of compounds with core protein had structural specificity (Deres K., Schroder C. H., Paessens A., et al. Science, 2003, 299 (5608):893-896). The study on its mechanism of action showed that through the action with 113-143 amino acid residues of core protein, HAP changed the angle between dimers forming nucleocapsid, thereby forming unstable swelled nucleocapsid, and accelerating the degradation of core protein (Hacker H. J., Deres K., Mildenberger M., et al. Biochem. Pharmacol. 2003, 66(12): 2273-2279). WO99/54326 and WO99/54329 respectively disclosed dihydropyrimidine compounds substituted by 2-pyridyl group and 2-thiazolyl group.